2.1. Synthetic Oligonucleotides and Their Utility
Oligonucleotides and, in particluar, oligodeoxynucleotides (DNA) enjoy a special status among the tools used by the scientific biological community. In its pursuit of knowledge regarding the intimate workings and details of the body's mechanism for expressing particular traits and the development of certain abnormalities and mammalian disease, sequence-specific oligonucleotides have been used in recombinant host-vector systems and, in diagnostic assays, as intermediates in the preparation of labeled oligonucleotide probes. DNA fragments of a few to tens of bases in length are useful models for the study of the local interaction of DNA with foreign agents or known therapeutic compounds (See, for example, Lippard et al. in Science 1985, 230, 412).
Recently, oligodeoxynucleotides, which are complementary to certain gene messager RNA or viral sequences, have been reported to inhibit the spread of disease related to viral and retroviral infectious agents (See, for example, Matsukura et al. in Proc. Natl. Acad. Sci. USA 1987, 84, 7706, and references cited therein). It has also been reported that oligonucleotides can bind to duplex DNA via triple helix formation and, presumably, inhibit transcription and/or DNA synthesis (See, Moser and Dervan in Science 1987, 238, 645).
These oligonucleotides are referred to as "antisense" compounds, and they, themselves, represent a whole class of therapeutic agents which exhibit antiviral activity and/or inhibit viral DNA synthesis or protein synthesis. Moreover, analogs of DNA having internucleotide phosphate linkages different from the phosphate diester groups of normal DNA have been found to possess their own unique characteristics which are desirable in certain applications. For example, methyl phosphonate analogs of DNA, perhaps being uncharged, demonstrate greater hydrophobicity and readily pass through cell membranes while inhibiting protein synthesis. The thiophosphate analogs are more resistant to degradation by nucleosides than their phosphate diester counterparts and are thus expected to have a higher persistence in vivo and greater potency. Phosphoramidate derivatives of oligonucleotides are known to bind to complementary polynucleotides and have the additional capability of accommodating covalently attached ligand species (See, for example, Froehler et al. in Nucleic Acids Res. 1988, 16(11), 4831).
Thus, oligonucleotides and their associated analogs have a well-established utility in biological and chemical research, but their synthesis is invariably time consuming, tedious, and costly.